Ophthalmologic Compositions And Use Mode Thereof

ABSTRACT

The invention concerns a pharmaceutical composition characterised in that it contains a combination of a parasympatholytic agent, a sympathomimetic agent and a local anaesthetic. Such a composition may be injected into the anterior chamber of the eye before a cataract operation or instilled on the eye before laser treatment.

BACKGROUND OF THE INVENTION

The present invention concerns the therapeutic field and moreparticularly the ophthalmologic field.

It more particularly deals with new pharmaceutical compositions for thetreatment of pain and/or lesions of the eye during surgical or physicaloperations or prior to an operation on the eye.

Its subject is more precisely compositions based on a parasympatholyticagent, an adrenergic substance and advantageously a local anaesthetic,in the context of pre-operative treatment of the eye for a surgicaloperation on cataracts or laser treatment of the retina. These activeingredients are to be administered simultaneously on or in the eye.

According to a particularity of the invention, the parasympatholyticagent is a mydriatic agent and preferably a derivative of tropic acidsuch as a tropic acid ester or a tropic acid amide or a cyclohexyl orcyclopentylacetic acid amide.

Among these parasympatholytic agents, we shall notably mentioncyclodrine, eucatropine, homatropine as well as atropine (benzylic esterof tropic acid), N-methyl hyoscine and especially tropicamide (N-ethyl2-phenyl N-4 pyridyl methyl hydracrylamide or pyridyl methyl benzeneacetamide).

Among the local anaesthetics, we shall more particularly mentionbutocaine, prilocaine, procaine, novocaine, tetracaine, ambucaine,amylocaine, bupivacaine, carticaine, butoxycaine, formocaine,mepivacaine, etidocaine, prilocaine, orthocaine, oxybuprocaine orbenoxinate, and mainly lidocaine or diethylamino 2,6 dimethylacetanilide, or one of its salts.

Among the adrenergic substances, we shall more particularly mentionnoradrenaline, phenylephrine, isoprenaline, dipivefrine, dimetrophine,norfenefrine, pholedrine or octedrine.

Combinations of this type have already been described in the literature.

Notably, the publication by Behndig A et al (Acta OphthalmologicaScandinavica (2004) 82(2) 144-147) describes the use of a compositioncontaining 0.1% cyclopentolate, 1.5% phenylephrine and 1% lidocaine,designed for intracameral administration in the context of a surgicaloperation by phacoemulsification.

In this publication, the results obtained by intracameral injection ofmydriatics were compared with those obtained by topical application. Theeffects, and especially the side effects, are no different. It appearsto be important with this technique to avoid the general effects relatedto the administration of epinephrine or the intracameral administrationof lidocaine.

Another publication (L. Apt et al. Am J. of Ophthalmology 89(4) (1980)553-559) describes the use of ophthalmologic compositions containingtropicamide (0.5% or 1%) or cyclopentolate (0.5%) combined withphenylephrine at 2.5%, in instillation in the eye, one drop in each eye.In certain cases, instillation of the combination of two mydriaticagents is preceded by topical application of a drop of the anaestheticproparacaine at 0.5%. The combination of three active ingredients is notenvisaged, however.

Furthermore, S. A. Miller and W. F. Mieler have demonstrated (Canad. J.Ophtal 13 (1978) 291-293) the systemic effects resulting fromsubconjunctival injection of a combination of phenylephrine at a veryhigh concentration (3.3%), cocaine (local anaesthetic at 1.3%) andatropine (0.3%), notably leading to an increase in blood pressure. Thisincrease was followed by hypotension, pulmonary oedema and endocardialischemia. The authors conclude by insisting on the dangerous effects onblood pressure of phenylephrine applied to the eye.

These triple combinations, notably the use of cyclopentolate as aparasympatholytic agent, at the concentrations indicated, are excludedfrom this invention.

These references, considered as the most similar in the prior art, showthe need to effectively combine strong pharmacological action and nearlytotal absence of general effects resulting from the resorption in theeye of drugs having systemic effects.

DESCRIPTION OF THE INVENTION

The compositions according to the invention are of major interest,notably in intracameral injection, for preparing the eye before asurgical operation or during the surgical operation, notably in thesurgical treatment of cataracts. As the volume of the intracameralchamber does not exceed 300 μl in man, the volume of the compositioninjected should preferably be less than or equal to 200 μl, notablybetween 50 and 200 μl.

The compositions according to the invention can also be administered ina collyrium beforehand or during a laser intervention on the retina.Typically, 1 to 5 drops (generally at a volume between 20 and 40 μl) areinstilled, which also represents a volume less than or equal to 200 μl.

It is important to point out that the compositions according to theinvention are capable of providing very rapid anaesthesia as well asnearly instantaneous, sizeable and sustainable dilation of the pupil forundertaking an examination of the pupil and the surgical operation asquickly as possible. It should also be pointed out that the anaesthesiais of long duration, so that the subject suffers little from theoperation they undergo. Such a combination has the advantage ofreinforcing the mydriatic effect of the parasympatholytic derivative,but without manifesting an overly long effect which leads to a decreasein vision essentially characterised by prolonged mydriasis. The effectsof mydriasis mainly translate into disturbances of vision and balance.

It therefore appeared that the ratios of active ingredients would haveto be determined with precision.

The compositions according to the invention can be distinguished fromthose described in the prior art by a concentration of a sympathomimeticagent, for example phenylephrine, that is sharply reduced.Advantageously, the concentration of the parasympatholytic agent is alsoreduced.

A combination of just two mydriatic agents is thus distinguished fromthe solutions in the prior art by low concentrations of sympathomimeticagents, or even parasympatholytic agents.

Advantageously, a composition according to the invention also contains alocal anaesthetic agent.

The pharmaceutical compositions according to the invention containbetween 0.001 and 0.6% parasympatholytic agent, between 0.04 and 0.5%sympathomimetic agent, and possibly between 0.2 and 3% local anaestheticagent.

A preferred composition contains between 0.01 and 0.5% parasympatholyticagent defined above, between 0.5 and 1.5% local anaesthetic and between0.1 and 0.4% sympathomimetic agent.

An ophthalmologic composition according to the invention, highlypreferred, contains between 0.015 and 0.025% parasympatholytic agent,advantageously tropicamide, between 0.75% and 1.25% lidocaine andbetween 0.2 and 0.4% phenylephrine in a single preparation. Such aformulation is particularly well suited to injection into the anteriorchamber of the eye before the surgical treatment of cataracts. For this,an incision is made at the time of the operation in the anterior chamberof the eye and the composition is injected into it. This preparation ofthe eye simultaneously causes mydriasis and local anaesthesia, allowingthe later extraction of the lens under favourable conditions. In thisprecise case, a single injection of a volume of the preparation between0.05 and 0.2 ml provides the desired effect.

In the case of a laser operation, the concentrations of thepharmaceutical compositions instilled are advantageously adapted.Notably, the concentrations of the parasympatholytic agent and localanaesthetic agent will be significantly higher, in the higher values ofthe widest range of concentrations. Thus, preferably, the concentrationsof the parasympatholytic agent will be between 0.1 and 0.25% and theconcentration of the local anaesthetic agent will be between 2 and 3%.Such preparations being designed for a single use, the use of apreservative may not be necessary. The preparations according to theinvention therefore may not contain any preservatives. In thissituation, the method of administration may also be different,proceeding with the instillation of the preparation on the treated eyein two to four times at one minute intervals. Thus, sedation of pain isensured more immediately and for a longer time.

According to the invention, the three active ingredients are dissolvedor dispersed in an aqueous vehicle, advantageously sterile. Thecompositions according to the invention may come in liquid or solidform, for example in the form of collyriums, single-dose recipients,instillable preparations, ready-to-use or in freeze-dried form to bereconstituted with an aqueous solvent when used.

The compositions according to the invention may also come in a mixedform, for example one of the active ingredients being freeze-dried to bereconstituted by adding an aqueous solution containing the other activeingredients. It is also possible to have a bottle containing one of thesolid active ingredients, covered by a frangible membrane above whichcan be found the solution containing the other active ingredients.

The invention will be better defined using the examples below:

EXAMPLE 1

Single-use preparation (strong dose) for intracameral injection prior toa surgical operation:

Tropicamide 0.00024 g

Phenylephrine (hydrochloride) 0.0038 g

Lidocaine (hydrochloride) 0.00917 g

Water for the injectable preparation in sufficient quantity for a 1-mlbottle for single use

The preparation according to the invention is to be administered byinjection into the anterior chamber of the eye (intracameral zone).

Said preparation could be presented in a single packaging for easyhandling with total safety, then administered to the patient in aquantity of liquid less than 1 ml, typically between 50 and 200 μl.

EXAMPLE 2

Single-use preparation (usual dose) for intracameral injection prior toa surgical operation:

Tropicamide 0.00016 g

Phenylephrine (hydrochloride) 0.00258 g

Lidocaine (hydrochloride) 0.00943 g

Water for the injectable preparation in sufficient quantity for a 1-mlbottle for single use

The preparation is used under the same conditions as in example 1.

EXAMPLE 3

Collyrium without preservatives with tropicamide for use prior to asurgical operation:

Tropicamide 0.05 g

Norepinephrine (hydrochloride) 0.02 g

Lidocaine (hydrochloride) 0.12 g

Sterile purified water 10 ml

Said preparation will be presented in single-use packaging.

EXAMPLE 4

Collyrium without preservatives for pre-laser administration:

Tropicamide 0.0015 g

Phenylephrine 0.030 g

Bupivacaine (hydrochloride) 0.25 g

Sterile purified water in sufficient quantity for 10 ml

Said preparation will be presented in single-use packaging. Thiscollyrium is particularly well suited to the treatment of pain duringlaser treatment.

The collyriums according to the invention are to be instilled on theeye, in three times one drop during the same day.

1.-12. (canceled)
 13. Pharmaceutical composition containing acombination of a parasympatholytic agent, a sympathomimetic agent and alocal anaesthetic, wherein: a concentration of the parasympatholyticagent is between 0.015 and 0.025%; a concentration of the localanaesthetic is between 0.75 and 1.25%; and a concentration of thesympathomimetic agent is between 0.2 and 0.4%.
 14. Pharmaceuticalcomposition as claimed in claim 13, wherein the parasympatholytic agentis tropicamide.
 15. Pharmaceutical composition as claimed in claim 13,wherein the local anaesthetic is selected from among butocaine,mepivacaine, tetracaine, carticaine, butoxycaine, orthocaine andlidocaine, or one of its salts.
 16. Pharmaceutical composition asclaimed in claim 13, wherein the sympathomimetic agent is selected fromamong phenylephrine, isoprenaline, dipivefrine, norfenefrine, pholedrineand octedrine.
 17. Pharmaceutical composition as claimed in claim 13,wherein the parasympatholytic agent is tropicamide, the localanaesthetic is lidocaine and the sympathomimetic agent is phenylephrine.18. Pharmaceutical composition as claimed in claim 13, wherein thepharmaceutical composition comes in a form of a solution or aqueoussuspension, in a single-dose bottle or a freeze-dried preparationreconstituted or to be reconstituted when used.
 19. Pharmaceuticalcomposition of claim 13, wherein the composition comprises a preparationof a medicine to be injected into an anterior chamber of an eye before asurgical operation on a lens or retina, notably for a cataractoperation.